‘’After more than 20 years since the last major revision, now is the time to update the regulatory framework for variations to simplify and adapt it to keep pace with scientific development. This will benefit patients by decreasing the risk for shortages and ensuring swifter access to innovative medicines and optimise life-cycle management to ensure the availability of safe, effective and innovative treatments to patients in a timely manner.’’ - Pär Tellner, Simon Bennett & Markus Goese

Background

The submission of information to regulators does not end with a medicine being approved. Medicine developers are required to continuously update the terms of their marketing authorisation to reflect the current understanding of the quality, safety and efficacy of a medicine. The current EU legal framework for managing these updates, the EU Variation Regulation and Classification Guideline[1], is inflexible, outdated and is associated with a very high administrative burden both for industry and for regulators. Therefore, there is a pressing need to modernise the variation framework for human medicines in order to support future innovation in medicine development and manufacturing within the EU. Moreover, it should be a priority to revise the EU variation framework in the light of recent experience with the COVID-19 pandemic which underlined the necessity for a flexible and agile regulatory system in Europe that can rapidly respond to the needs of patients by guaranteeing the optimization of life-cycle management to deliver safe and effective treatments of high quality to patients[2].

The time is now

A comprehensive revision of the Variation Regulation (1234/2008) and the associated Classification Guideline (C(2013) 2804) is essential to deliver simplification, well-organized life-cycle management and to adapt to latest technological developments such as digitalization. This also includes addressing challenges that link to the increasing number of medicines associated with devices, as well as for novel and more complex therapies, such as cell- and gene/ advanced therapies (ATMPs). Meanwhile, for the EU, there is an opportunity to continue playing a leading role in driving international alignment across variation systems thereby improving lifecycle management at a global level. The time for action is now and we are pleased to see this on the Commission Workplan for Q4 2023, because:

• There are many challenges due to resource constraints within the EU regulatory network. Implementing a streamlined variation framework with accompanying advances in Information Technology to reduce the administrative burden for variations could release resources for use in other areas such as scientific advice and assessment of new medicines.
• The full incorporation of risk-based approaches to lifecycle management, together with potentially embedding some regulatory flexibilities adopted during the COVID-19 pandemic would support innovation in the EU, particularly in manufacturing and quality where advances in this area are often implemented via the variation framework. A very important modality to benefit from such full incorporation of a risk- and science-based approach would be well defined biologics (e.g. monoclonal antibodies), where industry has made significant progress over the last decades in terms of understanding the products and their manufacturing processes. The risk-based approach may also be extended beyond quality topics to include updates to labelling under certain circumstances.
• Lessons learned from the pandemic and expedited programs like PRIME have also demonstrated that post-approval lifecycle management continues to be a critical bottleneck under the current variation framework.
• On-going work on digital projects, portals, digital infrastructure and databases of the EMA and National Authorities serve as a building block for the future operational support to regulatory processes.
• Raising the modernisation of the variation framework as a priority now facilitates progress towards a future-state which could be aligned with modifications to the general EU pharmaceutical legislation.

Going forward

Going forward, it will be essential to build on experience and technical innovations to provide an EU variation framework that allows for efficient lifecycle management of medicines and vaccines today and which can also include future technological advances. Furthermore, revision to the EU change classification should incorporate all elements of the important international guideline ICH Q12 and accommodate developments of innovation and science to be “fit for the future”. This should preferably happen via regulatory guidance, to allow for regular review and updating, rather than embed the detailed provisions in a regulation.

In parallel, advances in digital technology should be exploited to reduce the administrative burden associated with the oversight of minor variations that have no impact on safety, efficacy or quality of a medicine. In the near-term this may involve the development or extension of EU databases to maintain administrative information. In the longer term, advances in cloud-based technology could be employed to enable real-time maintenance and oversight of the dossier by regulators, thereby negating the requirement for any type of additional submission or data entry by regulators and industry. The present variation regulation needs however to be revised to fully benefit from such rationalization.

Lastly, the current and future needs of Regulators and Manufacturers should be reflected in a future variation framework through simplification, standardization and acceleration to certify optimal delivery of medicines to patients at a global level and reduce drug shortages. This can be achieved by redefining existing concepts such as work-sharing methods and grouping to decrease time for review and approval of the change and its subsequent implementation. Additionally, the concept of work-sharing and regulatory reliance with other regulatory agencies outside of EU, should be considered. These processes offer several benefits involving faster overall approvals, reduced regulator and industry resources and can support regulatory harmonization. This could result in rapid global implementation of changes, including in the EU[3].

Conclusion

EFPIA recommends that the EC and EMA fully implement the principles and tools described in ICH Q12 guidance in the future EU variation system and legislation. In addition, the future variation framework should assist a lifecycle management of medicines in being more efficient and tailored to new important modalities (e.g. ATMPs) and drug-device combination products as well as accommodate for the latest IT technological advances and digitalisation. In order to nurture European innovation, a revision of the EU variation framework needs to be tackled now. We owe it to European patients to ensure optimal and faster delivery of life-changing medicines throughout their lifecycle.

[1] https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:334:0007:0024:EN:PDF

[2] https://www.medicinesforeurope.com/wp-content/uploads/2020/01/ESE_2019_Medicine-for-Europe_AESGP_Variation_WEB.pdf

[3] https://www.medicinesforeurope.com/wp-content/uploads/2020/01/ESE_2019_Medicine-for-Europe_AESGP_Variation_WEB.pdf